Chronic kidney disease (CKD) is a relatively new concept for a disease proposed by the National Kidney Foundation (NKF) of the United States in 2002. As to the cause therefor, there are various systemic diseases and renal diseases and typical ones are diabetes mellitus, hypertension, chronic nephritis, etc. CKD is defined as such ones where any of the following (1) and (2) or both continue(s) for three months or more. They are:
(1) The case where the existence of nephropathy is clear as a result of urine test, image and pathological diagnosis, blood test, etc. and particularly where not less than 0.15 g/gCr of proteinuria (not less than 30 g/gCr of albuminuria) is detected. (The unit “/gCr” means “per gram of creatinine”.)
(2) The case where glomerular filtration rate (GFR) lowers to an extent of less than 60 mL/minute/1.73 m2. (GFR will be mentioned later.)
As a result of an increase in the occurrence frequency of life style-related diseases such as diabetes mellitus and hypertension in recent years, CKD is also increasing steadily. For example, it has been mentioned that the numbers of patients with CKD in Japan are 13,300,000 and reaches about 13% (one patient in about eight persons) of the adult population (“Guide for Diagnosis of CKD—2012” edited by the Japanese Society of Nephrology).
The first problem when one suffers from CKD is that the renal function lowers whereby waste products and water are unable to be excreted. As a result, dropsy is generated or one feels languid. In addition, vomiting, headache and anorexia are resulted due to uremia. Further progress thereof induces complications such as cardiovascular diseases (CVD) such as myocardial infarction, cardiac failure and cerebral apoplexy and pulmonary edema whereby crisis of life becomes high.
When end-stage kidney disease (ESKD) is resulted as the progress of the CKD, dialysis and kidney transplantation are necessary. For example, in Japan, patients who need the dialysis are steadily increasing and, in 2011, they were more than 300,000. That is one of the causes of swelling the national medical expenses and is a big problem in view of medical economy as well. Moreover, because dialysis treatment is to be done usually three times a week and requires four to five hours for each dialysis, that is a big burden in the daily life of a patient and greatly deteriorates the QOL. Accordingly, it is important to try not to result in a state where the dialysis treatment is necessary due to the occurrence of ESKD and also to try to retard the stage of initiating the dialysis treatment as long as possible. (The CKD before the start of the dialysis treatment as such is called “CKD in a conservative stage”.) In view of the above, there has been a brisk demand for pharmaceutical agents having a suppressive effect for the progress of CKD and exhibiting a high safety.
Human renal function is expressed by a glomerulus rate (CFR) which is the amount of plasma per unit time by all glomerular bodies in the kidney. A decrease in GFR means a decrease in the renal function. As a result thereof, metabolites in the body such as creatinine (Cr) and blood urea nitrogen (BUN) are unable to be excreted into urine but are accumulated in the body. As a reflection thereby, data of creatinine and BUN become high in the blood test. For precisely measuring the GFR, a troublesome test called inulin clearance or creatinine clearance is necessary. However, in the daily diagnosis where such a test is difficult, there has been used a simplified method in which serum creatine (sCr) value is measured by a blood test and, based on said value together with age and sex, an estimated glomerular filtration rate (eGFR) is calculated. For example, a calculation formula for eGFR suitable for the Japanese is proposed in “Evidence-based Practice Guidelines for the treatment of CKD—2013” edited by the Japanese Society of Nephrology), etc. In addition, the stage of CKD is roughly classified into five (the first stage to the fifth stage). Since the GFR value in the third stage (stage 3) or higher is less than 60 mL/minute/1.73 m2 (as hereinafter, the unit for the GFR value will be omitted), that is the CKD (refer to the above definition for CKD in (2)). When the GFR is less than 15, that is the fifth stage (stage 5) and is ESKD.
The GFR value in a healthy person is 60 or more. In a patient with CKD of stage 3 and more where the GFR value is less than 60, metabolites such as creatinine begin to be accumulated in blood whereby serum creatinine value and blood urea nitrogen value begin to rise significantly. In a slowly progressive patient where the GFR value worsens to an extent of only less than 10 in one year, the time until becoming ESKD whereby dialysis is to be introduced is still left to some extent. In such a patient, there is conducted a measure where progress of the disease is made to retard by a therapy where blood pressure and blood sugar are normalized, a smoking cessation therapy and a diet therapy where ingestion of salt and protein is restricted so as to prevent to become ESKD (Therapies as such are called “conservative therapy” of CKD.). Since hypertension is the biggest risk factor for the occurrence and the progress of CKD and also for the occurrence of CVD, control of blood pressure is particularly important. As to an antihypertensive, angiotensin-converting enzyme (ACE) inhibitor and angiotensin II receptor blocker (ARB) have been mainly used in combination, depending upon a patient, with diuretic agent, calcium antagonist, etc.
The time-dependant changes of the renal function in CKD can be aware of by means of chronological plotting of the GFR values. Thus, when a graph is drawn where an ordinate is for the eGFR value while an abscissa is for the time (stage), a worsening speed of the renal function can be noted. It is general in CKD that the GFR value linearly lowers from upper left to lower right. When the slope of this line is made as small as possible by means of a diet therapy or a drug therapy, the stage where ESKD is resulted and a dialytic treatment is necessary can be retarded.
The time-dependant changes in the renal function in CKD is also able to be aware of by plotting the reciprocal serum creatine (sCr) values (1/sCr; hereinafter, it will be sometimes called “reciprocal sCr value”). That is because the reciprocal sCr value is proportional to the GFR value. When the renal function is evaluated by the sCr value, ranges of normal standard values are usually within a ranges of 0.5 to 1.1 mg/dL and 0.4 to 0.8 mg/dL (hereinafter, the unit will be omitted) for males and females, respectively. Since creatinine is produced in muscles, its amount is proportional to the muscle amount and, generally, that in males is higher than that in females to an extent of 10 to 20%. In addition, it rarely varies depending upon the age. In elderly persons, the renal glomerular filtration rate lowers with the age but, since the muscle amount also decreases therewith, the sCr value becomes nearly constant. In case the renal function is evaluated by means of the sCr value, a follow-up observation will be necessary in some cases when the values in male and female reach 1.2˜1.3 and 0.9˜1.0, respectively. Generally, in moderate CKD, the sCr value exceeds 1.5 and, in a critical condition, it is 2.4 or even more. When the sCr value exceeds 5, recovery is difficult and the stage where the sCr value is 10 is a yardstick for starting the dialysis. Generally, in the actual site of medical care, it is common that an appropriate treatment is investigated by observing the elapse of GFR values, reciprocal sCr values or sCr values for several months to know the worsening velocity of CKD of a patient.
In patients with CKD, there are those in such a type where slope of a straight line plotted by GFR values or that plotted by reciprocal sCr values (hereinafter, the latter will be called “slope of reciprocal sCr values”) is relatively gentle and those in such a type where the slope is steep. For the former patients, it is possible to some extent to retard the progress to ESKD (to extend the period of CKD in a conservative stage) by a diet therapy or a drug therapy. However, for the patients where the GFR value or the reciprocal sCr value rapidly lowers and worsening of the symptom proceeds, there has been almost no therapeutic agent which effectively suppresses it. Once the patient reaches ESKD, dialysis is necessary in addition to a diet therapy and a drug therapy and QOL of the patient is very much deteriorated as mentioned already.
Under such circumstances, a spherical adsorptive carbon as a pharmaceutical agent has been approved in Japan where the indication is “improvement in uremic symptom in progressive chronic renal failure and retardation of introduction of dialysis”. In short, this agent is activated carbon. When this agent is ingested (each 2 g, three times daily, 6 g in total), uremic toxin in a patient with CKD is adsorbed with an intestine and excreted together with feces whereby there is achieved an effect of improving the uremic symptom and of retarding the introduction of dialysis. For example, according to the package insert for “Kremezin (Registered Trade Mark)” which is the original spherical adsorptive carbon preparation in Japan, the slope of reciprocal sCr values was significantly improved to −222±378×10−5 dL/mg·week (hereinafter, the unit will be omitted) from −329±245 before the administration in a clinical test (double-blind test) where said preparation was administered in a daily dose of 6 g per day (three times 2 grams) for 24 weeks to “patients with progressive chronic renal failure”. (In a placebo group, the data before and after the administration were −293±184 and −274±279, respectively.) In view of the above, there is no doubt that “Kremezin (Registered Trade Mark)” is an epoch-making drug which brought the big gospel to the patients with CKD. According to “Interview Form of Pharmaceutical Agent” for said agent, it has been sold in Asian countries such as Korea, Taiwan and the Philippines since its approval in Japan in 1991 although it has not been sold in Europe and America.
Incidentally, even a spherical adsorptive carbon preparation which is an epoch-making pharmaceutical agent, there are still some problems. Firstly, the spherical adsorptive carbon preparation has a problem that a dose of 6 g per day which is very high amount as a pharmaceutical agent should be ingested. Dosage forms of the spherical adsorptive carbon preparations sold in Japan are capsule and fine granules (powdered drug). With regard to the capsule, since one capsule contains 200 mg of the ingredient, one must ingest ten capsules at a time. Therefore, its daily dose is 30 capsules. Since that made the compliance of patients bad, another dosage form additionally approved in 2000 is fine granules (powdered drug). In the fine granules, since one pack contains 2 g, one pack at a time is ingested with water. When the fine granules are not well swallowed, the inner area of the mouth sometimes becomes entirely black. Therefore, it is recommended to swallow with some modifications such as to swallow after wrapping with a bag-shaped wafer (after dividing into several wafers if necessary) or to suck through a straw after being sunk in water in a cup. This should be conducted three times a day. In addition, it sometimes happens that, when the spherical adsorptive carbon preparation is ingested, the feces become black. In view of the above, there is a problem that the compliance upon ingestion of the spherical adsorptive carbon preparation is still bad. Moreover, the spherical adsorptive carbon preparation sometimes causes a side effect such as constipation or anorexia. When constipation happens, the effect of this drug decreases as well. In addition, since the spherical adsorptive carbon preparation adsorbs a chemical substance, when, for example, another pharmaceutical agent for hypertension or diabetes mellitus is administered together, there is a big problem that the active ingredient of the pharmaceutical agent is also adsorbed resulting in a decrease in the effect. Therefore, in a package insert for the spherical adsorptive carbon preparation, there is a description reading “When another agent is used together, it is to be taken into consideration that this agent is an adsorbent and the ingestion of another agent together with this agent should be avoided” as the “important fundamental notice” whereby ingestion together with another agent at the same time is prohibited. Under the current circumstances as such, there has been a brisk demand for the development of pharmaceutical agents for a patient with CKD where the effect is excellent, the side effect is little, the ingestion is easy and the simultaneous ingestion with another agent is possible.
The present compound (5-Hydroxy-1-methylhydantoin) was created by Nippon Zoki Pharmaceutical Co., Ltd. who is the applicant for the present application (Japan Patent Laid-Open No. sho-57-114578 and Japanese Patent No. 1,616,338). After that, the present compound was found to be effective for renal failure due to the suppression of production of uremic toxin (Patent Document 1). In Patent Document 1, there is described that the present compound has an action of lowering the uremic toxin such as urea nitrogen and creatinine in animal experiments using the rats with chronic renal failure induced by oral administration of adenine. However, there is no description therein at all for the optimum dose of the present compound to humans and also for the fact that, in case what type of a CKD-suffering patient is administered with the present compound, the effect for suppressing the progress of CKD can be significantly achieved.
In the meanwhile, the results of clinical tests of the present compound were presented at the meetings in 1997 and 1999 (Non-Patent Documents 1 and 2). In those documents, it is shown that the present compound suppresses the lowering of the reciprocal sCr value (1/sCr) of a patient with diabetic chronic renal failure (hereinafter, it will be referred to as “diabetic CRF”). However, pharmaceutical effects of the present compound are not compared after dividing the symptoms of patients into progressive and non-progressive ones. In addition, the effect of the present compound shown by those clinical test results cannot be said to be so significant and no development of the present compound has been conducted thereafter. Incidentally, the Non-Patent Documents 1 and 2 will be mentioned later in detail under the columns of Referential Example.